The binding of interferons to distinct cell surface receptors leads to the induction of synthesis of several unique polypeptides and their corresponding mRNAs (1)(2)(3)(4)(5)(6) (8,9). One of these cDNA clones is complementary to the mRNA for a 56-kDa protein (8), and the other, to the mRNA for 2',5'-oligo(A) synthetase (9), both of which are prominent IFN-induced protein products (7). Whether this increase in specific mRNA is based on increased transcription and/or increased stabilization of the mRNA in the cytoplasm has not been determined.In fact, whether transcriptional increases underlie the numerous biologic effects mediated by the binding of peptide hormones, growth factors, and lectins to their specific plasma membrane receptors is at present largely unknown. It is also unclear whether a polypeptide can effect an increase in specific mRNA concentration, particularly by transcriptional control, without entering the cell. Molecules such as cyclic AMP or Ca2+ or analogous "second messengers" could mediate the transcriptional stimulation of specific genes after an initial hormone-receptor interaction. Likewise, the effect of intracellular tyrosine kinase activities of membrane receptor proteins is under intense investigation, but no specific transcriptional activations have been documented as a result of these enzyme activities.A few cases have been analyzed that support the hypothesis of second messengers as transcriptional activators. Thyrotropin-releasing hormone (TRH) and epidermal growth factor (EGF) increase transcription of the prolactin gene in a pituitary cell line (10, 11). The effects of TRH can be mimicked by cyclic AMP treatment of the pituitary tumor cells. EFG-induced prolactin mRNA accumulation requires extracellular Ca2 , which implies that increased free intracellular
Expression of the human immunodeficiency virus type 1 (HIV) protease in cultured cells leads to apoptosis, preceded by cleavage of bcl-2, a key negative regulator of cell death. In contrast, a high level of bcl-2 protects cells in vitro and in vivo from the viral protease and prevents cell death following HIV infection of human lymphocytes, while reducing the yields of viral structural proteins, infectivity, and tumor necrosis factor a. We present a model for HIV replication in which the viral protease depletes the infected cells of bcl-2, leading to oxidative stress-dependent activation of NFKB, a cellular factor required for HIV transcription, and ultimately to cell death. Purified bcl-2 is cleaved by HIV protease between phenylalanine 112 and alanine 113. The results suggest a new option for HIV gene therapy; bcl-2 muteins that have noncleavable alterations surrounding the HIV protease cleavage site.
Background: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. Results: We have synthesized DMP 450 (his-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of IO mg kg-t DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in viva assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC,, suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. Conclusions: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.
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